The invention relates to delivery of therapeutic agents, and more particularly to a method and apparatus for in vivo delivery of therapeutic agents through the skin or mucosa using an electromotive force such as electroporation or iontophoresis.
Electroporation, which includes electropermealization, involves the creation of aqueous pathways in lipid bilayer membranes by the application of a brief electric field pulse. Electroporation has found wide-spread application in molecular biology and in transgenics as a method of introducing DNA or other material to a cell by momentarily charging the cell with a high voltage. In recent years, this technique has also been applied to the delivery of therapeutic agents through skin or mucosa. A pore or opening is created in the skin or mucosa by an electric field created by the positive and negative differential between two electrodes. This reversible path or route (pore) created using electroporation increases the membrane (skin, mucosa) penetration of a substance. However, there have been problems in placing electrodes and establishing the proper relationship between the position of the electrodes.
In addition, multiple administrations have required multiple applications of electrodes and therapeutic agents, entailing repeated affixing and removing of electrodes, thereby irritating the site tissue. Similarly, delivery of therapeutic agents over a long period of time or multiple applications of voltage have required multiple alternating applications of electrodes and therapeutic agents. In constructing an actual device, difficulties have arisen in containing the therapeutic agents on the surface of the electrodes and in placing the surface containing therapeutic agents and the surface of the electrodes in direct contact with the skin. Thus, conventional devices which use electroporation have unresolved problems.
It is known that it is possible to further increase the permeation of therapeutic agents using electroporation and iontophoresis jointly. lontophoresis uses electrical current to activate and to modulate the diffusion of a charged molecule across a biological membrane, such as the skin, in a manner similar to passive diffusion under a concentration gradient, but at a facilitated rate. In general, iontophoresis technology uses an electrical potential or current across a semipermeable barrier using an iontophoretic electrode pair, an iontophoretic electrode (anode or cathode) and a counter electrode. To jointly use electroporation and iontophoresis, an iontophoretic electrode must be placed in the same compartment (in the same device) as an electroporation electrode pair. While there are examples of in vitro experiments using electroporation and iontophoresis jointly, conventional techniques have not been able to create a device which can practically jointly use both types of electrodes.
Accordingly the inventor has determined that it would be desirable to have a method or device which would provide the following capabilities not provided by conventional techniques:
(1) simple administration of therapeutic agents using an electroporation electrode pair via skin or mucosa;
(2) application of electrodes for long periods of time and application of voltage multiple times without requiring multiple applications and removals of electrodes;
(3) simultaneous application of electric field pulses for electroporation and a pharmaceutical composition containing a therapeutic agent; and
(4) joint utilization of electroporation and iontophoretic electrodes.
The present invention provides such capabilities.
A permeable membrane which is porous and is used to support electrodes for electroporation is useful for substantially continuous controlled delivery of a therapeutic agent through the skin or mucosa, when placed in direct contact with the skin or mucosa and by application of electric field pulses at specified intervals. The electroporation electrodes can be affixed to this porous membrane to form an electrode membrane. In addition, an electrode membrane can be assembled such that it can incorporate an iontophoretic electrode in the same device. This device can be jointly utilized for electroporation and iontophoresis. In addition, a device which has this kind of electrode membrane is practically useful and easily manufactured.